Mechanism of Action of Compound-13: An α1-Selective Small Molecule Activator of AMPK

Abstract

SummaryAMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.

Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori -induced oxidative stresses and gastric epithelial cell apoptosis

“…1A) [18], we successfully synthesized this novel AMPK activator. We examined whether GECs were response to this newly synthesized compound.…”

“…1B and C). Since C13 is an a1-selective small molecule activator of AMPK, it induces activation of AMPK through interaction with a1 subunit [18]. Next, we tested the role of AMPKa1 in C13-mediated AMPK activation in GES-1 cells.…”

“…[18]. Anti-AMPKa1, AMPKa2, acetyl-CoA carboxylase (ACC), and b-tubulin antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA).…”

“…In this study, we investigated the potential role of compound 13 (C13), an a1-selective small molecule activator of AMPK [18], against H. pylori-induced GEC apoptosis. Our results show that C13 exerts GEC protective activity against H. pylori through activating AMPK-heme oxygenase (HO-1) signaling.…”

Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP)

“…As we proposed before, one possibility is AMP activation of AMPK, but the mechanism appears more complex because of the following reason. By using AMPK-deficient mice, it was determined that metformin and other small molecular weight compounds such as A769662, a known activator of AMPK, were not effective in inhibiting lipogenesis completely in hepatocytes (14). Metformin is the most widely used drug to treat type 2 diabetes, but the molecular mechanism of its action is unknown.…”